Method of producing {60 -carboxylated 5-membered lactones

ABSTRACT

Five-membered lactones are Alpha -carboxylated by reacting in solution the lactone with methyl methoxy-magnesium carbonate. The lactone reactants are restricted to those having an Alpha methylene group.

United States Patent Parker et al.

[451 Oct. 10, 1972 [54] METHOD OF PRODUCING a- CARBOXYLATED S-MEMBERED LACTONES [73] Assignee: The Dow Chemical Company,

Midland, Mich.

[22] Filed: Nov. 10, 1969 [21] App]. No.: 875,520

[52] US. Cl. ..260/326.3, 260/247.2 B, 260/3433,

260/3436 [51] Int. Cl ..C07d 27/28, C07d 5/06, C07d 5/46 [58] Field of Search ..260/343.6, 326.3, 343.3

[56] References Cited OTHER PUBLICATIONS Herman L. Finkbeiner et a1. Chelation as a Driving Force in Organic Reactors, J. A.C.S. Vol. 85 616 (1963).

Primary ExaminerAlex Mazel Assistant Examiner-Anne Marie T. Tighe Att0rneyGriswold & Burdick and C. E. Rehberg [5 7] ABSTRACT Five-membered iactones are a-carboxylated by reacting in solution the lactone with methyl methoxy-magnesium carbonate. The lactone reactants are restricted to those having an a-methylene group.

9 Claims, No Drawings BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION It has now been discovered the a-carboxylated 5- membered lactones, i.e., 'y-butyrolactones, are produced in the novel process comprising reacting in solution a S-membered lactone having an a-methylene group with methyl methoxymagnesium carbonate, i.e., Stiles Reagent (J.A.C.S., 85, 616 (1963)).

The initial product of the subject process is a chelate formed between the magnesium ion and the desired acarboxylactone. It is therefore necessary to acidify the reaction mixture after the chelate is formed to obtain the free a-carboxylactone.

Suitable lactone reactants in the subject process may be represented by the structural formula wherein R and R are hydrogen or an inert organic group. By inert, we mean inert in the process. Suitable lactone reactants include those of formula I wherein R, and R are hydrogen, or organic groups having up to about 25 carbon atoms, said groups being alkyl, aryl, alkaryl, aralkyl, alkoxy, aryloxy, cycloalkyl, five and six-membered heterocyclicalkyl wherein the hetero atom isoxygen or nitrogen, or a hydrocarbon whose chain length is interrupted with a keto, ester or carboxamide group, or R, and R are joined to form a five or six-membered cycloaliphatic group, a heterocyclic alkyl group wherein the hetero atom is oxygen or nitrogen, or a five-membered lactone group, and other like compounds. Preferred reactants are those wherein R, is hydrogen and R is hydrogen or an organic group of one to about carbon atoms or R, is joined with R to form a five or six-membered cycloaliphatic group, a

heterocyclicalkyl group wherein the hetero atom is ox- 6 ygen or nitrogen, or a five-membered lactone group. The most preferred reactants are those wherein (a) R, is hydrogen and R is hydrogen or an alkyl group of one to about l0 carbon atoms, (b) R, is joined with R to form a five-membered lactone. or (c) R, is hydrogen and R, is

Examples of suitable lactone reactants include those set forth in Table I.

TABLE I H H H methyl butyl methyl H nor iso-propyl H cyclohexyl H n-octyl H n-dodecyl 'n butyl H n-decyl H H phenyl H tolyl H xylyl H benzyl H Z-phenethyl ethoxy H H butoxy H OC,,H N-morpholmo H i H CHgCHg-Q-CHg H H CH1CHZCOC7H5 n H l1CaHuCN H-,v

CH3 H C4HgN I H CHzC N and compounds wherein R and R arev joined to form fused rings, such as and other like compounds.

The methyl methoxymagnesium carbonate or Stiles reagent may be prepared by any known convenient methodbut is advantageously prepared by the method described by H. L. Finkbeiner and M. Stiles, J.A.C.S., 85, 616 (1963).

The reaction is preferably conducted in solution. Any inert organic liquid solvent is suitable, such as cyclic and straight-chain aliphatic ethers, and more polar solvents, such as N,N-dimethyl formamide, and the. like. Examples of suitable solvents include ethyl ether, tetrahydrofuran (THF), N,N-dimethyl formamide (DMF), dimethylsulfoxide, and hexamethylphosphoramide and other like compounds and mixtures thereof. DMF is the preferred solvent.

The reaction requires at least one mole of methyl methoxymagnesium carbonate per mole of lactone, and a molar excess of carbonate reactant is preferred, such as about 4 or 5 moles of carbonate per mole of lactone. At a reactant molar ratio above about 5, little advantage is realized, and when the molar ratio is less than 1, the product yield is lowered. The reaction temperature is suitably between about 60C. and about 200C, and is preferably between about 100C. and about 150C. The reaction temperature is typically and conveniently governed by the boilin g point of theschosen solvent.

The reactionpressure is not critical and atmospheric, superatmospheric or subatmospheric pressures can be suitably used. Atmospheric pressure, or pressures slightly above, are convenient and therefore preferred.

The reaction rate varies in a direct manner with the reaction temperature, and in an inverse manner with the size or bulk of the R and R substituents, particularly with. the R, substituent, due to steric effects. Generally, a suitable reaction time is between about 1 and about 24 hours and is preferably between about 5 to about 8 hours under the preferred conditions of temperature, etc.

To maximize product yields, it is important to conduct the reaction under substantially anhydrous conditions since water attacks and deactivates the carbonate reactant. It is also advantageous to conduct the reaction under an .inert atmosphere, such as dry nitrogen, and, it is seemingly important to removethe methanol from the'reaction mixture essentially as it is formed since methanol substantially reduces the reaction rate. In practice, a dry inert gas is merely passed through the reaction mixture to (1) establish a dry, inert atmosphere and (2) remove the methanol; or, the reaction is conducted under reduced pressure at a temperature such that .the methanol is removed. Other equivalent and obvious methods, however, may be used.

Preparation of Standard Methyl Methoxymagnesium Carbonate (MMC) Solution added slowly to 8 l. of dry methanol over a 16 hour" period. After the magnesium was completely reacted,

the excess methanol was removed under reduced pressure. DMF was added to give a volume of 10 l. and

gaseous carbon dioxide was added to the stirred soluslow stream of CO at an elevated temperature. The solution was cooled to room temperature and stirred under CO for l-3 hours.

Example 1. The preparation of a-Carboxy-y- Phenylbutyrolactone stream of dry nitrogen passing through the reaction I mixture. 6N HCl was then added with agitation until the precipitate dissolved. The reaction mixture was then extracted 4 times with portions of ethyl ether. The extracts were combined, washed with saturated. aqueous sodium bicarbonate, the aqueous phase was acidified with HCI, extracted with ether and the ether solution separated, washed with water, and dried over magnesium sulfate. The drying agent was filtered off, the ether removed at 40C. under reduced pressure, and the pale yellow oil residue was crystallized by triturating same with carbon tetrachloride. The product was a cis-trans mixture which was resolved by crystallization from a 50-50, volume basis, petroleum ether (b.p. 5060C.)-ethyl ether solvent mixture. The chemical structure of the cis isomer, which was the major product, was confirmed by nuclear magnetic resonance (NMR) and elementalv analysis- Melting point: 103-104c.

TABLEll %C %H Calc. 60.39 7.43 Found 60.57 7.58

Example 2. The Preparation of a-Carboxy-B-( ll-lydroxynonyl)-8-Oxol -Pyrrolidinevaleric Acid 'y- A sample of II (1.0 g.) was mixed with 5.0 ml. of the above standard solution of MMC. The reaction mixture was heated at C. for 26 hours with a continuous stream of dry nitrogen passing through the reaction mixture. The product was isolated using an identical workup procedure as in Example 1. The chemical structure of the product was confirmed by NMR and infrared (IR) and elemental analysis. Melting point: 92-95C.; Product yield: 85 percent.

TABLE Ill %c %H %N Calc. 64.56 8.84 3.96 D?! 64-1 8- 9 12 Methylation of III using diazomethane gave the cor- Example 3. The Preparation of a-Carboxylated 2- H ydroxy-3-( l-Hydroxynonyl)Glutaric Acid diy- Lactone HA noocp 0 A sample of IV (2.77 g., 10.9 mmol) was mixed with 22 ml. of the above standard solution of MMC. The reaction mixture was heated at 120C. for 5 hours with a continuous stream of dry nitrogen passing through the reaction mixture. The solution was poured into a mixture of ethyl ether 100 ml.) and 6N HCl 100 ml.). The mixture was shaken until the precipitate dissolved. The ether phase was separated, washed 4 times with water, washed once with a saturated aqueous NaCl solution, dried over MgSO and then concentrated to an oil under reduced pressure. The oil crystallized upon standing. The product was recrystallized from a hexane-ethyl ether mixture. Weight: 2.43 g. (75 percent yield); melting point: 7880C. The chemical structureof the product was confirmed by NMR, IR and elemental analysis.

TABLE IV %C %H Calc. 60.39 7.43 Found 60.57 7.58

Example 4. The Preparation of (2- Hydroxyoctyl)Malonic Acid y-Lactone COOH i=0 on on 0 CHSTCHZ 6 0 3 2 6 0 (VII) A sample of VI (2.0 g., 11.75 mmoles) was mixed with 20 ml. of the above standard solution of MMC. The reaction mixture was heated at 140C. for 6 hours 'with a continuous stream of dry nitrogen passing TABLE V %c %H Calc. 61.66 8.47 Found 61.56 8.73

(2-Hydroxyhexyl)malonic acid 'y-lactone was prepared from f .11 on on inasimilar manner. I A

We claim:

1. A process for producing an a-carboxylated 'y-butyrolactone comprising reacting by contacting in solution (a) a 'y-butyrolac'tone having two hydrogen atoms on the a-carbon, with (b) methyl methoxymagnesium carbonate; said process being conducted at a reaction temperature of from about C. to about 200C.

2. The process defined in claim 1 wherein the y-carbon atom of (a) bears an alkyl substituent of from one to 10 carbon atoms.

3. The process defined in claim 1 tyrolactone.

4. The process defined in claim 1 wherein (a) has the f l wherein (a) is y-bu- CE: O n H I l: 2

wherein R and R are joined to form a five-membered lactone ring. 7 5. The process defined in claim 1 wherein (a) is wherein said alkyl group has from one to 10 carbon aton1s,or

CE: O $11-$11 1'1. 1'1.

wherein R and R are joined to form a five-membered lactone ring. 

2. The process defined in claim 1 wherein the gamma -carbon atom of (a) bears an alkyl substituent of from one to 10 carbon atoms.
 3. The process defined in claim 1 wherein (a) is gamma -butyrolactone.
 4. The process defined in claim 1 wherein (a) has the formula
 5. The process defined in claim 1 wherein (a) is
 6. The process defined in claim 1 wherein the temperature is between about 100*C. and about 150*C. and the molar ratio of (b): (a) is at least
 1. 7. The process defined in claim 6 wherein said molar ratio is between 1 and 5, and wherein the reaction is conducted in dimethyl formamide.
 8. The process defined in claim 7 wherein the reaction is conducted in dimethyl formamide.
 9. The process defined in claim 7 wherein (a) is gamma -butyrolactone or a gamma -butyrolactone of the formula 